You are here
Therapeutic Monitoring of Prostate Cancer Drugs - Romano Danesi at PC Debate, Baveno, April 2016
Professor Romano Danesi,
Department of Clinical and Experimental Medicine, University of Pisa, Italy
Prostate Cancer Debates, Baveno, April 2016
Drug-drug interactions are common in clinical practice because patients often receive several drugs at the same time. This interaction may result in a different profile of drug sensitivity and adverse reactions. The newer anti-hormonal agents like abiraterone and enzalutamide used in the treatment of prostate cancer are of special interest because they modulate the metabolism of drugs in the liver. Therapeutic drug monitoring should be considered to avoid excessive exposure and the risk of toxicity states Professor Romano Danesi, Department of Clinical and Experimental Medicine, University of Pisa, Italy.
Good afternoon. My name is Romano Danes and I am a clinical pharmacologist in the University of Pisa, Italy. My group is involved in the therapeutic drug monitoring of anti-cancer drugs and, in our group, we do modelling of pharmacogenetic determinants of drug metabolism and therapeutic drug monitoring. This is an important area of work because many drugs interact with each other. For this reason, we expect a different profile of drug sensitivity and adverse reactions due to the interaction between drugs.
Particularly, we are very interested in prostate cancer drugs because many of the hormonal agents are also able to modulate the metabolism of the drugs at the hepatic level. In particular, we do therapeutic drug monitoring in order to discover different concentrations of drugs after treatment with hormonal agents, with standard agents for the treatment of other diseases such as cardiovascular or metabolic or, for instance, anti-infective drugs.
Monitoring of newer anti-hormonal medications
In the case of the newer anti-hormonal agents in the treatment of prostate cancer, like enzalutamide and abiraterone, we try to adapt the drug concentration to the real need of the patient. In particular, when we have a drug interaction at the level of liver metabolism, we can have induction of enzyme activity, which results in the reduction in the concentration of the drug in the blood because, by reducing the enzyme activity, we increase the metabolic clearance of the drug. Under these circumstances, we have to monitor the patient closely, because a reduction in drug concentration in the blood may be associated with loss of efficacy and type F adverse drug reactions.
On the contrary, if we have enzyme inhibition, we have a reduction in enzyme and metabolism of the drug and, for this reason, we can have an increase in drug concentration and an increased risk of adverse drug reactions of A type – the so-called augmented – so more toxicity, due to inhibition of drug metabolism.
Modulation of hepatic metabolism by abiraterone and enzalutamide
Bearing this in mind, we should consider that, among the most recent drugs such as abiraterone and enzalutamide, we have a different profile of potential drug interactions. In the case of abiraterone, this is an inhibitor of CYP2D6. CYP is an acronym for cytochrome p450: these are oxidases located in the liver, which participate in the metabolism of the drug by oxidising the substrate. The substrate is then subjected to Phase II chemical reactions in the liver.
In the case of abiraterone, we have an inhibition of drug metabolism at the level of CYP2D6, and this could result in an increase in the concentration of drugs metabolised by CYP2D6. On the contrary, we know that enzalutamide is a strong inducer of CYP3A4: CYP3A4 is probably the most important isoform of CYP enzymes present in the liver, because CYP3A4 metabolises more than 60 per cent of all drugs given to an individual. For this reason, an increase in the enzyme activity may result in a decrease in drug concentration and loss of efficacy – the so-called type F adverse drug reaction.
Therapeutic index and therapeutic window
Drug/drug interactions should be put into a wider context. This is not only a question of how much one drug interacts with another, but we should also consider the therapeutic index of drugs – because drugs with a wide therapeutic index are less likely to be associated with adverse drug reactions. On the contrary, drugs with a narrow therapeutic index are frequently associated with adverse drug reactions.
Another consideration is the therapeutic window - in other words, this is the minimum and maximum concentration of the drug to reach pharmacological efficacy. If a drug goes up in terms of drug levels associated with toxicity, and this is typically associated with the drug inhibition of enzyme metabolism in the liver, we should be careful and monitor the patients for type A adverse drug reactions.
In conclusion, we should consider that drug/drug interactions are very common in clinical practice, because patients usually receive more than two drugs in combination. We should be aware of the potential risk of drug/drug interactions and we should also be able to prevent them by knowing the metabolic pathways associated with specific drug metabolism. In case the drug interaction is strong, we should be able to address the importance of such an interaction by doing therapeutic drug monitoring, by measuring the drug concentration in the blood in order to avoid excessive exposure and the risk of toxicity.